1. Field of the Invention
The present invention relates to methods for preventing, inhibiting or treating graft-versus-host disease (GVHD) and graft rejection reactions in organ transplantation.
2. Prior Art
In bone marrow transplantation or blood transfusion, or organ transplantation from a donor to a recipient having no histocompatibility with the donor, the donor's lymphocytes migrate into the recipient. If the recipient cannot reject the donor's lymphocytes, the donor's lymphocytes take and proliferate in the recipient's body. Then the lymphocytes attack tissues with the guidance of antigens carried exclusively by the recipient, thus inducing disorders.
In 1959, Mathe et al. reported for the first time graft-versus-host disease (GVHD) in a leukemic patient after having bone marrow transplantation. The major symptoms of GVHD include frequent fever, anthema, diarrhea, vomiturition, anorexia, abdominal pain and hepatopathy. GVHD breaks out in patients having non-autogenous myeloma cells and induces in some cases lethal diseases such as systemic erythroderma or hepatic insufficiency. When an immunodeficient patient has the transplantation of an organ which is rich in immunocompetent cells, there arises a high risk of the onset of graft-versus-host reactions. Therefore, it is an important problem to prevent and treat GVHD in infants or children who suffer from primary immunodeficiency and are going to have bone marrow transplantation for reconstructing the immune system or patients who are going to have bone marrow transplantation for treating malignant diseases.
Bone marrow transplantation is a therapeutic which comprises breaking a host's hemic system and transplanting the bone marrow, i.e., a mass of cells serving as the basis of the hemic system of a healthy donor to the host so as to reconstruct in the host's body a hemic system originating in the donor. Essential factors for the success in marrow transplantation include the take of a graft, the regulation of graft-versus-host reactions and the immunological reconstruction. About one week after the bone marrow transplantation, the leukocyte count of the host attains the minimum level and thus the host is liable to suffer from bacterial or fungal infection. Acute GVHD frequently breaks out at this stage. To prevent GVHD, it is a practice to give an immunosuppressant cyclosporin A (CsA) optionally together with, for a short period of time, methotrexate (MTX). At the onset of acute GVHD, prednisolone and cyclosporin A are administered. The treatment of acute GVHD with the use of these drugs is restricted due to the side effects thereof, for example, hypertension, renal function disorder and an increase in the recurrence rate of leukemia. Namely, it is believed that cyclosporin A relates to the onset of nephrotoxicity, bone marrow depression, hypertension, hemolytic-uremic syndrome, hyperglycemia, shock, hypomagnesemia, and, in particular, atherosclerosis in heart transplantation. Also, it is known that prednisolone relates to induced infectious diseases, peptic ulcer, etc., while methotrexate relates to bone marrow depression, hepatic/renal function disorder, mucosal disorder, psychoneurosis, interstitial pneumonia, pulmonary fibrosis, etc.
On the other hand, chronic GVHD breaks out 70 to 400 days after transplantation. It is classified into three types of 1) progressive onset following acute GVHD, 2) quiescent occurring once acute GVHD disappears, and 3) de novo newly occurring without the onset of acute GVHD. Compared with acute GVHD, chronic GVHD causes organ derangement over a broad range and thus induces the appearance of autoantibodies in many cases. Although it has been a practice to administer cyclosporin A and prednisolone to treat chronic GVHD, which is known to be observed in 30 to 60% of patients with bone marrow transplantation, no satisfactory effect can be achieved thereby.
Under these circumstances, it has been urgently required to develop remedies for GVHD which are highly efficacious against acute GVHD and chronic GVHD and have a high safety.
The first case of organ transplantation was renal transplantation effected in 1950's. About 30 renal transplantations were performed in USA, France, etc. till 1960. In those days, exposure of patients to radiation was the only method for inhibiting the graft rejection reactions (immune suppression). Thus, the rejection reactions could not be controlled well, which made it impossible to successfully perform the transplantation. The only successful case of renal transplantation was one effected between identical twins where no rejection reaction arose. Subsequently there have been developed immunosuppressants such as azathioprine, prednisolone, cyclosporin A, methotrexate and tacrolimus (FK 506): Inorgan transplantation, in particular, the appearance of cyclosporin A results in a remarkable increase in the ratio of successful transplantations. However, the long-term administration of the immunosuppressants brings about various side effects and complications, which makes the postoperative QOL not always favorable. It is reported that the side effects of azathioprine include bone marrow depression, hepatic disorder, pancreatitis, digestive tract symptoms, cardiopalmus and respiratory disorder, while those of tacrolimus (FK 506) include renal function disorder, shock, elevation of blood pressure, heart failure, pancreatitis, hemolytic-uremic syndrome, thrombotic thrombopenia, purpura and hyperglycemia. Also, prednisolone, cyclosporin A and methotrexate exhibit similar side effects as those described above.
Retinoic acid plays important roles in the growth and retention of functions in animals, for example, specifically regulating the differentiation and proliferation of cells and participating in the morphogenesis of vertebrates. Concerning these physiological functions, retinoic acid has attracted public attention as a carcinostatic or a specific remedy for proliferative skin diseases (psoriasis, keratosis, etc.). Thus, there have been synthesized a number of retinoic acid analogs. Recently, there has been pointed out the presence of more than one retinoic acid receptor subtype, though the physiological meaning thereof has never been clarified so far (The Retinoids, 2nd ed., Raven Press, Ltd., New York, 1994, Sporn, M. B., Roberts, A. B., Goodman, D. S.).
On the other hand, it has been known for a long time that vitamin A closely relates to the immune system. It has been frequently reported that retinoic acid, which is an oxidative metabolite of vitamin A, would exert a suppressive effect on the immune system. For example, Brinckerhoff et al. reported that secondary inflammation in rat adjuvant arthritis was significantly suppressed by administering 13-cis-retinoic acid (Science 221, 756, 1983.). Recently, Kuwabara et al. reported that rat collagen arthritis was significantly ameliorated and the blood anticollagen antibody titer was lowered by administering retinoic acid receptor-.alpha. agonists (FEBS Letters, 378, 153, 1996.).
It has been disclosed hitherto that retinoic acid receptor agonists are usable in treating cancers such as leukemia, mammary cancer, prostatic cancer, lung cancer, esophageal and respiratory tract cancer, skin cancer and bladder cancer, skin diseases such as psoriasis, keratosis, eczema, atopic dermatitis, acne and Darier's disease, autoimmune diseases such as rheumatoid arthritis and lupus erythematosus, inflammations in organs over a broad range such as chronic polyarthritis, spondylathritis and arthrosis deformans, and allergic or rheumatic immunological diseases, in U.S. Pat. No. 4,703,110, JP-A-2-76862, JP-A-63-255277, JP-A-8-505359, etc. However, there has been no report suggesting that retinoic acid receptor agonists are applicable to GVHD in bone marrow transplantation or retinoic acid receptor agonists inhibit graft rejection reactions in organ transplantation.